Human CCR5high effector memory cells perform CNS parenchymal immune surveillance via GZMK-mediated transendothelial diapedesis

Herich, Sebastian; Schneider‐Hohendorf, Tilman; Rohlmann, Astrid; Ghadiri, Maryam Khaleghi; Schulte‐Mecklenbeck, Andreas; Zondler, Lisa; Janoschka, Claudia; Ostkamp, Patrick; Richter, Jannis; Breuer, Johanna; Dimitrov, Stoyan; Rammensee, Hans‐Georg; Grauer, Oliver; Klotz, Luisa; Groß, Catharina C.; Stummer, Walter; Missler, Markus; Zarbock, Alexander; Vestweber, Dietmar; Wiendl, Heinz; Schwab, Nicholas

doi:10.1093/brain/awz301

Cited by 40 publications

(50 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, fingolimod treatment was associated with elevated frequencies of CD56 + memory T cells, and increased granzyme (GZM) B, perforin, and Fas ligand expression in memory T cells in MS patients, and interestingly, this T cell phenotype was also associated with clinical relapses [192]. Additionally, Herich et al demonstrated that CD4 + T EM expressing high levels of CCR5 and GZMK are involved in CNS immune surveillance in healthy individuals, but that this subset was dominant in peripheral blood mononuclear cells of MS patients, and that natalizumab (anti-α4-integrin) treatment significantly decreased these cells [193]. Furthermore, the CCR5 high GZMK + CD4 + T EM subset shares many transcriptional features with T RM and Th17 cells, suggesting that it could play a central role in CNS pathology [193].…”

Section: Autoreactive T CM and T Em Subsets And Disease-modifying Thementioning

confidence: 99%

“…Additionally, Herich et al demonstrated that CD4 + T EM expressing high levels of CCR5 and GZMK are involved in CNS immune surveillance in healthy individuals, but that this subset was dominant in peripheral blood mononuclear cells of MS patients, and that natalizumab (anti-α4-integrin) treatment significantly decreased these cells [193]. Furthermore, the CCR5 high GZMK + CD4 + T EM subset shares many transcriptional features with T RM and Th17 cells, suggesting that it could play a central role in CNS pathology [193].…”

Section: Autoreactive T CM and T Em Subsets And Disease-modifying Thementioning

confidence: 99%

See 1 more Smart Citation

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Raphael

Joern

Forsthuber

2020

Cells

108

View full text Add to dashboard Cite

CD4 + T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4 + Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4 + T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4 + tissue-resident memory T cells and of CD4 + memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4 + T cell-mediated autoimmune diseases.

show abstract

Section: Autoreactive T CM and T Em Subsets And Disease-modifying Thementioning

confidence: 99%

Section: Autoreactive T CM and T Em Subsets And Disease-modifying Thementioning

confidence: 99%

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Raphael

Joern

Forsthuber

2020

Cells

108

View full text Add to dashboard Cite

show abstract

“…We assume that cells at different stages undergo different processes. A total of four possible cell stages X in R 4 , two for the compartments (PB, CSF) and two for naïve and differentiated lymphocytes, respectively, are considered. Transition between all stages will be described next.…”

Section: Mathematical Modellingmentioning

confidence: 99%

“…Under homeostatic conditions these barriers regulate transmigration of distinct immune-cell subsets into the CNS [1]. As a consequence, the immune-cell profiles differ between peripheral blood (PB) and cerebrospinal fluid (CSF) and only distinct immune-cell subsets, mainly fulfilling immune-surveillance functions, are detectable in the CSF of healthy individuals [2][3][4]. Under autoinflammatory conditions, barrier dysfunction and/or hyperactivation of immune-cell subsets results in increased migration of pathogenic lymphocytes into the CNS [5].…”

Section: Introductionmentioning

confidence: 99%

“…For some invertible 4 × 4 matrix A and a 4 × 1 vector b, both depending linearly on α 1 , α 2 , β 1 , and β 2 . Provided we have k = 1,..,K, experimental measurements of cell distributions in all four stages given, i.e., X k in R 4 , we use the model to estimate the rates α 1 , α 2 , β 1 , and β 2 . Since we do not have information on possible measurement error on the experimental data we consider an unweighted and unbiased least-square formulation to obtain optimal rates α = (α 1 , α 2 ) and β = (β 1 , β 2 ).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Generation of a Model to Predict Differentiation and Migration of Lymphocyte Subsets under Homeostatic and CNS Autoinflammatory Conditions

Groß

Pawlitzki

Schulte‐Mecklenbeck

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

The central nervous system (CNS) is an immune-privileged compartment that is separated from the circulating blood and the peripheral organs by the blood–brain and the blood–cerebrospinal fluid (CSF) barriers. Transmigration of lymphocyte subsets across these barriers and their activation/differentiation within the periphery and intrathecal compartments in health and autoinflammatory CNS disease are complex. Mathematical models are warranted that qualitatively and quantitatively predict the distribution and differentiation stages of lymphocyte subsets in the blood and CSF. Here, we propose a probabilistic mathematical model that (i) correctly reproduces acquired data on location and differentiation states of distinct lymphocyte subsets under homeostatic and neuroinflammatory conditions, (ii) provides a quantitative assessment of differentiation and transmigration rates under these conditions, (iii) correctly predicts the qualitative behavior of immune-modulating therapies, (iv) and enables simulation-based prediction of distribution and differentiation stages of lymphocyte subsets in the case of limited access to biomaterial. Taken together, this model might reduce future measurements in the CSF compartment and allows for the assessment of the effectiveness of different immune-modulating therapies.

show abstract

Differential Runx3, Eomes, and T‐bet expression subdivides MS‐associated CD4⁺ T cells with brain‐homing capacity

Hoeks,

Puijfelik,

Koetzier

et al. 2023

Eur J Immunol

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4+ T cells are assumed to be the first to cross the blood–central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity‐associated effector programs define CD4+ T cell subsets with brain‐homing ability in MS. Runx3‐ and Eomes‐, but not T‐bet‐expressing CD4+ memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3+Eomes+T‐bet− enrichment in cerebrospinal fluid samples of treatment‐naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6+CXCR3+CCR4−/dim). Previously published CD28− CD4 T cells were characterized by a Runx3+Eomes−T‐bet+ phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady‐state conditions, granzyme Khigh Th17.1 cells spontaneously passed the blood–brain barrier in vitro. This was only found for other subsets including CD28− cells when using inflamed barriers. Altogether, CD4+ T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood–brain barrier as a possible early event in MS.

show abstract

Human CCR5high effector memory cells perform CNS parenchymal immune surveillance via GZMK-mediated transendothelial diapedesis

Cited by 40 publications

References 89 publications

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Generation of a Model to Predict Differentiation and Migration of Lymphocyte Subsets under Homeostatic and CNS Autoinflammatory Conditions

Differential Runx3, Eomes, and T‐bet expression subdivides MS‐associated CD4⁺ T cells with brain‐homing capacity

Contact Info

Product

Resources

About

Human CCR5high effector memory cells perform CNS parenchymal immune surveillance via GZMK-mediated transendothelial diapedesis

Cited by 40 publications

References 89 publications

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Generation of a Model to Predict Differentiation and Migration of Lymphocyte Subsets under Homeostatic and CNS Autoinflammatory Conditions

Differential Runx3, Eomes, and T‐bet expression subdivides MS‐associated CD4+ T cells with brain‐homing capacity

Contact Info

Product

Resources

About

Differential Runx3, Eomes, and T‐bet expression subdivides MS‐associated CD4⁺ T cells with brain‐homing capacity